An urgent need exists for new and more effective antimalarials. Preliminary studies indicate that when the Chinese traditional medicinal drug, artemisinin, is covalently bonded through an ester linkage to poly(ethylene glycol) (PEG), the resulting molecule has much higher antimalarial activity than artemisinin. With the long-range goal of developing PEG-artemisinins as useful antimalarial drugs, the following initial experiments will be conducted during Phase I of this project: (a) the possibility of improving antimalarial activity will be evaluated in in vitro Plasmodium falciparum assays using branched PEG and pendant PEG ester derivatives of artemisinin to increase drug loading and by optimizing the molecular weight of the attached PEGs to increase drug loading and by optimizing the molecular weight of the attached PEGs (b) the stability of PEG linked artemisinins will be evaluated by hydrolysis rate measurements in serum and in rats of several PEG derivatives. (c) uptake of PEG-linked artemisinin in P. falciparum cells will be assessed using double-labeled PEG-artemisinin esters and (d) neurotoxicity of PEG-artemisinin in rats will be evaluated. Plans for moving closer to a viable PEG-linked antimalarial in Phase II include studies in animals of antimalarial drug effectiveness, pharmacokinetics, and metabolism. PROPOSED COMMERCIAL APPLICATION Poly(ethylene glycol) derivatives of artemisinin have high potential for use as drugs for the treatment of malaria.